The overarching goal of Project II is to identify the defining characteristics of disease neurons in Williams syndrome (WS), and to address the interplay between gene expression and the WS social phenotype. Genetic reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells or iPSCs) by over-expression of specific genes has been accomplished using mouse and human cells. The resulting iPSCs are isogenic to the donor individual, i.e., they carry a similar genetic background, and thus are attractive not only for future therapeutic purposes, with lower risk of immune rejection, but also for the understanding of complex diseases with heritable and sporadic conditions. Thus, the use of human iPSCs as a biological tool to understand complex disorders, such as WS, may provide additional insights into the disease pathology, and new compounds that ameliorate disease progression. Wth an unparalleled history of research on WS as a compelling model for understanding the linkages from molecular genetics to neurobiology to higher cognition and social functions, WS provides a privileged setting for the proposed studies. The remarkable potential of iPSCs has sparked profuse interest and excitement in researchers studying individuals with a variety of neurodevelopment disorders, because of their potential to reveal avenues for intervention. WS offers an excellent model due to a well-defined genetic basis and a robust social phenotype. To this end, the Specific Aims are: (1) to derive iPSCs from individuals with WS as well as typical controls; (2) to analyze the gene expression profile of neural cells derived from controls and WS iPSCs; and (3) to test cross-level hypotheses generated during the course of the Program Project, e.g., the role of specific genes in the atypical WS social behavior, neuronal phenotype, and brain anatomy. The pluripotent stem cells will be driven to differentiate in neurons for a comprehensive transcriptional analysis and future mechanistic explorations based on our hypotheses. The ultimate aim of this research is to discover potential biomarkers and specific therapeutic targets. Elucidating the links between genes and social-affective behavior in WS may provide fundamental insight into the genetic mechanisms and neural circuits responsible for human social behavior